Dysregulation of the immune system underlies many autoimmune and inflammatory diseases. While genetic contributions to disorders such as multiple sclerosis, type 1 diabetes and inflammatory bowel disease (IBD) are being studied, new research highlights the importance of environmental factors. The human microbiome, a consortium of microbes that colonize humans, has emerged recently as a critical contributor to disease. Gut bacteria regulate the development and function of the immune system, and have been strongly implicated in IBD and experimental colitis. Recent seminal studies have identified that specific gut bacteria can suppress intestinal inflammation in preclinical models. Thus development of probiotic therapies for IBD is a promising area of research. Our laboratory has described a leading model system for studying beneficial host-bacterial symbiosis. Bacteroides fragilis, a common member of the human microbiome, ameliorates gut inflammation and treats experimental colitis. We reveal striking new data that B. fragilis directly activates the autophagy pathway, and requires autophagy for its therapeutic activity. Autophagy is a cellular process whereby particles (such as pathogenic bacteria) are degraded and destroyed. Importantly, polymorphisms in autophagy genes are highly linked to human IBD. Our research uncovers a new role for autophagy, as a pathway that responds to beneficial bacteria and mediates immune suppression. This connection between the gut microbiome and autophagy has previously not been studied, and may have profound implications to the underlying cause(s) of IBD. This project will investigate novel mechanisms by which environmental (microbiome) and genetic (autophagy) factors merge to contribute to disease. We will test the hypothesis that genetic defects in autophagy may lead to IBD by not 'sensing' and responding to the protective signals of beneficial gut bacteria. Specific aims include: 1) Determining cellular and molecular requirements for B. fragilis activation of the autophagy pathway; 2) Exploring autophagy as a mechanism for amelioration of colitis; 3) Examining the requirement for autophagy in human cells activated by B. fragilis. These studies promise to uncover novel and fascinating interactions between gut bacteria and the immune system, by revealing a previously unappreciated link between the microbiome and autophagy. If successful, discoveries from this project will significantly advance our long-term goal of developing a safe and effective treatment for IBD.